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    Case Studies in NIPT: NIPT for detection of subchromosomal deletions and duplications

    Case Studies in NIPT pairs fascinating real case examples involving use of NIPT with commentaries from experts on practical clinical implications of the technology. This case was provided by Sequenom and peer reviewed by series co-chairs Joe Leigh Simpson, MD, and Ronald J. Wapner, MD.



    Introduction: Noninvasive prenatal testing (NIPT) has rapidly changed the prenatal landscape for pregnant women at increased risk of fetal aneuploidy. This technology provides high sensitivity and specificity for Trisomy 21, 18, and 13. Overrepresentation of a chromosome can be detected by an increased Z-score in comparison with a normal euploid genome. Here we report a case involving a partial chromosome 13 duplication that assisted in identifying a maternal balanced translocation and revealed the limitations of suboptimal karyotype resolution.

    Methods: Maternal plasma samples were subjected to DNA extraction and library preparation followed by massively parallel sequencing as described by Palomaki et al. Sequencing data were analyzed using a novel algorithm to detect trisomies and other subchromosomal events as described by Chen et al.

    Results: A 38-year-old G8P3043 presented for NIPT due to advanced maternal age and a previous pregnancy history of Trisomy 13, confirmed by low-resolution karyotype on peripheral blood. Ultrasound at 12 weeks, 6 days was suspicious for micrognathia. NIPT studies were ordered and results were positive for Trisomy 13. Sequencing data were reviewed based on the clinical history and revealed a 24.3Mb duplication of 13q31.2 and an apparent 27.85Mb deletion of 4q32.2. A fetal demise was noted on a 15 week, 0 day ultrasound. Products of conception (POC) studies were performed at 450–500 band resolution resulting in a normal female karyotype 46,XX, discordant from the NIPT results. Follow-up maternal studies at high-resolution karyotype analysis detected a balanced translocation: 46,XX,t(4;13)(q32;q31). After informing the tissue analysis laboratory of the translocation events, discordance between NIPT and POC studies was attributed to low karyotype resolution.

    Conclusion: This case demonstrates the power of NIPT sequencing technology and optimized bioinformatics. Clinicians should be conscious that standard karyotyping does not have sufficient resolution to detect subchromosomal events detected by NIPT. Accurate clinical information provided to the laboratory may aid in additional interpretation. In these cases, microarray studies or high-resolution karyotype should be used to confirm a suspected abnormality.


    NEXT: Commentary from Ronald J. Wapner, MD >>


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